Structural immunology,focusing on structures of host immune related molecules,enables the immunologists to see what the molecules look like,and more importantly,how they work together.Antibody-based PD-1/PD-L1 blockad...Structural immunology,focusing on structures of host immune related molecules,enables the immunologists to see what the molecules look like,and more importantly,how they work together.Antibody-based PD-1/PD-L1 blockade therapy has achieved brilliant successes in clinical applications.The recent breakthrough of the complex structures of checkpoint blockade antibodies with their counterparts,pembrolizumab with PD-1 and avelumab with PD-L1,have made it clear how these monoclonal antibodies compete the binding of PD-1/PD-L1 and function to blockade the receptor-ligand interaction.Herein,we summarize the structural findings of these two reports and look into the future for how this information would facilitate the development of more efficient PD-1/PD-L1 targeting antibodies,small molecule drugs,and other protein or non-protein inhibitors.展开更多
Antibody-based PD-IIPD-L1 blockade therapies have taken center stage in immunotherapies for cancer, with multiple clinical successes. PD-1 signaling plays pivotal roles in tumor-driven T-cell dysfunction. In contrast ...Antibody-based PD-IIPD-L1 blockade therapies have taken center stage in immunotherapies for cancer, with multiple clinical successes. PD-1 signaling plays pivotal roles in tumor-driven T-cell dysfunction. In contrast to prior approaches to generate or boost tumor-specific T-cell responses, antibody-based PD-1/PD-L1 blockade targets tumor-induced T-cell defects and restores pre- existing T-cell function to modulate antitumor immunity. in this review, the fundamental knowledge on the expression regulations and inhibitory functions of PD-1 and the present understanding of antibody-based PD-1/ PD-L1 blockade therapies are briefly summarized. We then focus on the recent breakthrough work concerning the structural basis of the PD-IIPD-Ls interaction and how therapeutic antibodies, pembrolizumab targeting PD-1 and avelumab targeting PD-L1, compete with the binding of PD-1/PD-L1 to interrupt the PD-1/PD-L1 interaction. We believe that this structural informationwill benefit the design and improvement of therapeutic antibodies targeting PD-1 signaling.展开更多
Blockade of PD-1/PD-L1 signaling pathway by monoclonal antibodies （MAbs） to release the anti-tumor activity of pre- existing tumor specific T cell immunity has initiated a new era for tumor immunotherapy. Administra...Blockade of PD-1/PD-L1 signaling pathway by monoclonal antibodies （MAbs） to release the anti-tumor activity of pre- existing tumor specific T cell immunity has initiated a new era for tumor immunotherapy. Administration of anti-PD-1 MAbs （nivolumab and pembrolizumab） in either monotherapy or in combination with anti-CTLA-4 MAbs or traditional chemother- apy has achieved a tumor regression rate of 30%-50% in dealing with melanoma, non-small cell lung cancer, etc. （Larkin et al., 2015）.展开更多
基金This work was supported by the Ministry of Science and Technology of China(973 program:2013CB531502)the National Natural Science Foundation of China(NSFC31390432 and 31500722).
文摘Structural immunology,focusing on structures of host immune related molecules,enables the immunologists to see what the molecules look like,and more importantly,how they work together.Antibody-based PD-1/PD-L1 blockade therapy has achieved brilliant successes in clinical applications.The recent breakthrough of the complex structures of checkpoint blockade antibodies with their counterparts,pembrolizumab with PD-1 and avelumab with PD-L1,have made it clear how these monoclonal antibodies compete the binding of PD-1/PD-L1 and function to blockade the receptor-ligand interaction.Herein,we summarize the structural findings of these two reports and look into the future for how this information would facilitate the development of more efficient PD-1/PD-L1 targeting antibodies,small molecule drugs,and other protein or non-protein inhibitors.
基金This work was supported by the National Basic Research Program （973 Program） （Nos. 2013CB531502 and 2014CB542503）, the National Natural Science Foundation of China （Grant Nos. 31390432 and 31500722）, Grand S＆T project of China Health and Family Planning Commission （2013ZX10004608-002 and 2016ZX10004201-009）, the Strategic Priority Research Program of the Chinese Academy of Sciences （CAS XDB08020100）. GFG is supported partly as a leading principal investigator of the NSFC Innovative Research Group （81321063）.
文摘Antibody-based PD-IIPD-L1 blockade therapies have taken center stage in immunotherapies for cancer, with multiple clinical successes. PD-1 signaling plays pivotal roles in tumor-driven T-cell dysfunction. In contrast to prior approaches to generate or boost tumor-specific T-cell responses, antibody-based PD-1/PD-L1 blockade targets tumor-induced T-cell defects and restores pre- existing T-cell function to modulate antitumor immunity. in this review, the fundamental knowledge on the expression regulations and inhibitory functions of PD-1 and the present understanding of antibody-based PD-1/ PD-L1 blockade therapies are briefly summarized. We then focus on the recent breakthrough work concerning the structural basis of the PD-IIPD-Ls interaction and how therapeutic antibodies, pembrolizumab targeting PD-1 and avelumab targeting PD-L1, compete with the binding of PD-1/PD-L1 to interrupt the PD-1/PD-L1 interaction. We believe that this structural informationwill benefit the design and improvement of therapeutic antibodies targeting PD-1 signaling.
文摘Blockade of PD-1/PD-L1 signaling pathway by monoclonal antibodies （MAbs） to release the anti-tumor activity of pre- existing tumor specific T cell immunity has initiated a new era for tumor immunotherapy. Administration of anti-PD-1 MAbs （nivolumab and pembrolizumab） in either monotherapy or in combination with anti-CTLA-4 MAbs or traditional chemother- apy has achieved a tumor regression rate of 30%-50% in dealing with melanoma, non-small cell lung cancer, etc. （Larkin et al., 2015）.
